ATP-dependent polynucleotide ligases catalyze phosphodiester bond formation using nicked nucleic acid substrates with the high energy nucleotide of ATP as a cofactor in a three-step reaction mechanism. DNA ligases play a vital role in the diverse processes of DNA replication, recombination and repair. ATP-dependent ligases are present in many organisms such as viruses, bacteriophages, eukarya, archaea and bacteria. There are three classes of ATP-dependent DNA ligases in eukaryotic cells (I, III and IV). DNA ligase III is not found in lower eukaryotes and is present both in the nucleus and mitochondria. It has several isoforms; two splice forms, III-alpha and III-beta, differ in their carboxy-terminal sequences. DNA ligase III-beta is believed to play a role in homologous recombination during meiotic prophase. DNA ligase III-alpha interacts with X-ray Cross Complementing factor 1 (XRCC1) and functions in single nucleotide Base Excision Repair (BER). The mitochondrial form of DNA ligase III originates from the nucleolus and is involved in the mitochondrial DNA repair pathway. This isoform is expressed by a second start site on the DNA ligase III gene. DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains. The adenylation and C-terminal oligonucleotide/oligosaccharide binding (OB)-fold domains comprise a catalytic core unit that is common to most members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many active site residues. The common catalytic core unit comprises six conserved sequence motifs (I, III, IIIa, IV, V and VI) that define this family of related nucleotidyltransferases.
Comment:Sealing a nick in DNA requires three catalytic steps: first, enzyme adenylation is accomplished using ATP resulting in an AMP-linkage to the enzyme; second, the AMP is transferred to the 5' phosphate at the site of a nick; and third, phosphoryl transfer and sealing the nick DNA.
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